11/15/2009 @ 6:18PM

Another Vytorin Mess For Merck

The results of a much-awaited study could hardly be worse for
Merck
‘s big-selling cholesterol drugs Zetia and Vytorin.

A small 208-person trial that used ultrasound to examine arteries found that Zetia was clearly inferior to a version of the old drug niacin in preventing clogged arteries. Moreover, in a surprise finding, patients on niacin appeared to have fewer heart attacks and were less likely to die from heart disease than those who got Zetia. It is unusual for such a small trial to show a difference in heart attack rates.

While the results are hardly definitive, top cardiologists said the findings provide yet another hint that Zetia–and its sister drug Vytorin–may do little or nothing to prevent clogged arteries and heart attacks above and beyond what cholesterol lowering “statins” like Lipitor can do alone. Cardiologists also say it provides evidence that niacin is not being used aggressively enough.

The new trial was supported by
Abbott Laboratories
and compared Abbott’s Niaspan, a proprietary formulation of niacin, to Zetia in heart patients. The results are the main event at American Heart Association meeting here and are also being featured in the New England Journal of Medicine. They come on the heels of another artery imaging study in 2008 that also showed that Zetia didn’t do much for clogged arteries.

“You can look at this and say, ‘is this the nail of the coffin of Zetia?’” says Anthony DeMaria, professor at the UC-San Diego and editor of the Journal of the American College of Cardiology. “For me I think not quite yet, but it’s getting closer and closer and closer.”

Merck
argues the results should be viewed not as an indictment of Zetia but as a triumph for niacin. The patients in the study were particularly likely to be helped by niacin, notes Merck senior vice president Luciano Rossetti, because they had low levels of good cholesterol, or HDL, which niacin boosts. Zetia’s main effect is to lower elevated levels of bad cholesterol, or LDL. And he says that many patients can’t tolerate the high doses of niacin used in the study as it causes patients’ faces to become uncomfortably pink.

Still, the new findings raise questions about whether the Food and Drug Administration approved Zetia prematurely without requiring big trials to show the drug can prevent heart attacks. The problem is that Zetia does not lower cholesterol in the same way as Lipitor, Crestor and other cholesterol-lowering “statin” drugs, which stop production of cholesterol in the liver.

“How is it possible for a drug to have $4 billion in sales without any evidence of benefit?” says Harlan Krumholz, a cardiologist at Yale University. He said that the small size of the two imaging studies mean they couldn’t render a clear verdict on Zetia. “But they don’t instill any confidence in it either. ” Douglas Weaver, head of cardiology at the Henry Ford Hospital in Detroit says: “ We’ve used Zetia without sufficient amounts of clinical data to support it. Using it may be right, it may be wrong, but we don’t know right now.”

Even some who have reservations about the new study are getting worried about Zetia. Roger Blumenthal of Johns Hopkins University wrote an editorial in the New England Journal of Medicine detailing various flaws in the new study, including the fact that it was stopped prematurely after only half the number of intended patients had completed the full study period.

But he says the weight of the evidence should still lead doctors to reach for Niaspan or other drugs over Zetia in many patients. Most of the 13 cardiologists who reviewed the paper for Forbes agree. “It’s a big win for Niaspan, and yet another disappointment for Zetia,” says Blumenthal.

Zetia and the combination pill Vytorin, which combines Zetia with the generic drug Zocor, together are Merck’s second biggest product with $4 billion in annual sales. They were the driving force behind Merck’s $41 billion purchase of
Schering-Plough
two weeks ago. But sales of the two have dropped 25% over the past two years as a string of negative results raised the possibility that Zetia and Vytorin may not prevent clogged arteries. Also during that period,
AstraZeneca’s
competing drug Crestor was shown to prevent heart attacks and save lives.

Zetia’s slide began two years ago when Forbes reported that Merck and then-partner Schering-Plough had delayed unveiling on another ultrasound imaging study, called ENHANCE, for more than a year. When those results were finally presented in January 2008, it turned out that the expensive Vytorin combo was no better at preventing arteries from thickening than its generic Zocor component alone.

At the time, Merck and Schering-Plough argued that the patients in the ENHANCE trial represented a special case. They all had a genetic disease that causes high cholesterol and had been treated for years with high doses of statin drugs like Zocor, Lipitor or Crestor. The intense treatment made it difficult for a new drug to show a difference, Merck’s argument went.

But the niacin study was conducted in more typical heart patients who had not taken statin drugs for years and years. Abbott’s drug reversed atherosclerosis, while Merck’s didn’t. “It certainly blunts that criticism enormously,” says UC-San Diego’s DeMaria.

The niacin study, led by cardiologists at Washington Hospital Center and Walter Reed Army Medical Center, used ultrasound to measure the thickness of patients’ neck arteries. Thicker arteries have more plaque. The arteries of patients who took niacin got slightly thinner over 14 months, indicating plaque was going away. But there was no improvement in the arteries of those on Zetia.

Moreover, nine patients taking Zetia died of heart problems, had heart attacks or needed heart surgery, compared with two on Niaspan. While statistically significant, the numbers are to small to draw firm conclusions, cardiologists said. “You need more than 200 events in a cardiovascular trial” to be confident about the results, says Terje Pedersen of Ullevål University Hospital in Norway.

Cardiologists were also highly critical of a decision to stop the trial about a year early, which severely limits the conclusions that can be drawn. Pedersen called the decision to stop early “completely ridiculous.” David Brown, head of cardiology at Stony Brook University Medical Center, says he “doesn’t know what the scientific basis for stopping came from” and that it “significantly weakened the study.”

Lead investigator Allen Taylor of Washington Hospital Center, who has done paid speaking for Abbott, says he had always planned an early look at his data. Upon seeing that the results were already statistically solid, he ended the study for ethical reasons. “You can’t sit with a patient and say, ‘Ma’am, will you come into this study?’ when you know the answer,” he says.

The only thing that is likely to resolve the controversy surrounding Zetia and Vytorin is a big trial showing the drugs prevent heart attacks. But Merck didn’t start such a trial until late 2005, a full three years after Zetia was first approved. Results won’t be available until at least 2012. John Kastelein of Utrecht Hospital in the Netherlands noted in another New England Journal editorial that the trial is so large and unwieldy that it may never yield a clear answer.

Merck says it is working hard as it can to get the big trial done. “We are doing everything we can,” says Merck’s Rosetti. “If I had [the results] faster I would love it.”